Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant

TLDR

Spike RBD binding to ACE2 is essential for viral entry, and the RBD is the dominant target for neutralizing antibodies with several epitopes already mapped. The study aimed to determine how SARS‑CoV‑2 mutations alter Spike antigenicity. To address this, the authors isolated and characterized over 100 monoclonal antibodies against RBD, NTD, and S2 from infected individuals. About 45 % of the antibodies neutralized virus, ~20 % were NTD‑specific, and NTD‑specific antibodies split into a highly potent group and a glycan‑dependent, less potent group; B.1.1.7 mutations frequently conferred resistance, highlighting the need to consider subdominant epitopes when evaluating antigenic drift.

Abstract

Interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the receptor ACE2 on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies, and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, N-terminal domain (NTD) and S2 subunits of Spike. To understand how these mutations affect Spike antigenicity, we isolated and characterized >100 monoclonal antibodies targeting epitopes on RBD, NTD, and S2 from SARS-CoV-2-infected individuals. Approximately 45% showed neutralizing activity, of which ∼20% were NTD specific. NTD-specific antibodies formed two distinct groups: the first was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Mutations present in B.1.1.7 Spike frequently conferred neutralization resistance to NTD-specific antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes should be considered when investigating antigenic drift in emerging variants.